The answer is unequivocally, “yes”In co-highlighting the papers from Need et al., 2009, and Tomppo et al., 2009, you pose the question “CNV’s, interacting loci or both?” to which my immediate answer is an unequivocal “yes,” but it actually goes further than that. These two studies, interesting in their own rights, add just two more pieces of evidence now accumulated from case only, case-control, and family-based linkage on the genetic architecture of schizophrenia. Thus, we can reject with confidence a single evolutionary and genetic origin for schizophrenia. If it were so, it would have been found already by the plethora of genomewide studies now completed, studies specifically designed to detect causal variants, should they exist, which are both common to most if not all subjects and ancient in origin—the Common Disease, Common Variant (CDCV) hypothesis.

Moreover, for DISC1, NRG1, NRXN1, and a few others, the criteria for causality are met in some subjects, but none of these is the sole cause of schizophrenia. Their net contributions to individual and population risk remain uncertain and await large scale resequencing as well as SNP and CNV studies to capture the totality of genetic variation and how that contributes to the incidence of major mental illness. Meanwhile, nosological and epidemiological evidence has also forced a re-evaluation of the categorical distinction between schizophrenia and bipolar disorder, let alone schizoaffective disorder (Lichtenstein et al., 2009).

In this regard, DISC1 serves again as an instructive paradigm, with good evidence for genetic association to schizophrenia, BP, schizoaffective disorder, and beyond (Chubb et al., 2008). The study by Hennah et al. (2008) added a further nuance to the DISC1 story by demonstrating intra-allelic interaction. Tomppo et al. (2009) now build upon their earlier evidence to show that DISC1 variants affect subcomponents of the psychiatric phenotype, treated now as a quantitative than a dichotomous trait. In much the same way and just as would be predicted, DISC1 variation also contributes to normal variation in human brain development and behavior (e.g., Callicott et al., 2005). Self-evidently, different classes of genetic variants (SNP or CNV, regulatory or coding) will have different biological and therefore psychiatric consequences (Porteous, 2008).

That Need et al. (2009) failed to replicate previous genomewide association studies (or find support for DISC1, NRG1, and the rest) is just further proof, if any were needed, that there is extensive genetic heterogeneity and that common variants of ancient origin are not major determinants of individual or population risk (Porteous, 2008). Variable penetrance, expressivity, and gene-gene interaction (epistasis) all need to be considered, but these intrinsic aspects of genetic influence are best addressed by family studies (currently lacking for CNV studies) and poorly addressed by large-scale case-control genomewide association studies. Power to test the CDCV hypothesis may increase with increasing numbers of subjects, but so does the inherent heterogeneity, both genetic and diagnostic.

That said, genetics is without doubt the most incisive tool we have to dissect the etiology of major mental illness. The criteria for success (and certainly for causality, rather than mere correlation) must be less about the number of noughts after the “p” and much more about the connection between candidate gene, gene variant, and the biological consequences for brain development and function. In this regard, both studies have something to say and offer.

The results reported by Tomppo et al. and Need et al. collectively instantiate the complexities of the genetic architecture underlying risk for psychiatric illness. Paradoxically, however, while the results of Need et al. suggest that the answer to the complex question of risk genes for schizophrenia (SZ) may be found by searching a very select population for rare changes in genetic sequence, the results of Tomppo et al. suggest that the answer may be found by searching for common variants in large heterogeneous populations. So which is it? Is SZ the result of rare, novel genetic mutations or an accumulation of common ones? Such a conundrum is not a novel predicament in the process of scientific inquiry and such conundrums are often resolved by the reconciliation of both opposing views. Thus, if we allow history to serve as our guide it seems reasonable that the answer to the current question of what genetic mechanisms are responsible for SZ, is that SZ is caused by both rare and common variants.

Although considerable efforts, by our lab and others, are currently being directed towards seeking the type of rare variants that Need et al. suggest may be responsible for risk for SZ, a less concerted effort is being directed towards parsing the effects of more specific, common genetic variations. To date, there are limited data seeking to elucidate the effects of previously identified risk variants for SZ on phenotypic variation within the diagnostic group. The data that are available, however, suggest that risk variants do influence phenotypic variation. Our work with DISC1, for example, has produced relatively robust, and replicated findings linking variation in the gene to cognitive dysfunction (Burdick et al., 2005) as well as an increased risk for persecutory delusions in SZ (DeRosse et al., 2007). Similarly, our work with DTNBP1 indicates a strong association between variants in the gene and both cognitive dysfunction (Burdick et al., 2006) and negative symptoms in SZ (DeRosse et al., 2006). Moreover, the risk for cognitive dysfunction associated with the DTNBP1 risk genotype was also observed in a sample of healthy individuals. Thus, it seems conceivable that genetic variation associated with phenotypic variation within a diagnostic group may also be associated with similar, sub-syndromal phenotypes in non-clinical samples.

The data reported by Tomppo et al. provide support for the utility of parsing the specific effects of genetic variants on phenotypic variation and extend this approach to populations with sub-syndromal psychiatric symptoms. Such an approach is attractive in that it allows us to study the effects of genotype on phenotype without the confound imposed by psychotropic medications. Although the current data linking genes to specific dimensions of psychiatric illness are provocative, the study groups utilized are comprised of patients undergoing varying degrees of pharmacological intervention. Thus, in these analyses quantitative assessment of psychosis is to some extent confounded by treatment history and response. By measuring lifetime history of symptoms, which for most patients includes substantial periods without effective medication, many studies (including our own) may partially overcome this limitation. Still, assessment of the relation between genetic variation and dimensions of psychosis in study groups not undergoing treatment with pharmacological agents would be a compelling source of confirmation for these preliminary findings.

Perhaps most importantly, the data reported by Tomppo et al. suggest that previously identified risk genes should not be marginalized but rather, should be studied in non-clinical samples to identity phenotypic variation that may be related to the signs and symptoms of psychiatric illness.

Has anyone considered the possibility that the CNVs found...
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Has anyone considered the possibility that the CNVs found to be elevated in schizophrenia versus controls could be a peripheral effect and perhaps not present in brain tissue? For example, the diet of the typical schizophrenia patient is poor, and it is conceivable that chronic folate deficiency could predispose to problems in DNA structure or repair in lymphocytes. Thus, the CNVs could be an effect of the illness, and not a cause. Someone needs to do the experiment that compares CNVs in blood to those in the brain of the same individual. And then we need studies of the stability of CNVs over the lifetime of an individual.

The papers by Need et al. and Tomppo et al. seem
to present conflicting evidence for the
involvement of common or rare variants in the
etiology of schizophrenia.

On the one hand, Need et al., in a very large and
well-powered sample, find no evidence for
involvement of any common SNPs or CNVs.
Importantly, they show that while any one SNP
with a small effect and modest allelic frequency
might be missed by their analysis, the likelihood
that all such putative SNPs would be missed is
vanishingly small. They come to the reasonable
conclusion that common variants are unlikely to
play a major role in the etiology of
schizophrenia, except under a highly specific and
implausible genetic model. Does this sound the
death knell for the common variants, polygenic
model of schizophrenia? Yes and no. These and
other empirical data are consistent with
theoretical analyses which show that the
currently popular purely polygenic model, without
some gene(s) of large effect, cannot explain
familial risk patterns (Hemminki et al., 2007;
Hemminki et al., 2008; Bodmer and Bonilla, 2008). It has been
suggested that epistatic interactions may
generate discontinuous risk from a continuous
distribution of common alleles; however, while
comparisons of risk in monozygotic and dizygotic
twins are consistent with some contribution from
epistasis, they are not consistent with the
massive levels that would be required to rescue a
purely polygenic mechanism, whether through a
multiplicative or (biologically unrealistic)
threshold model.

Thus, it seems most parsimonious to conclude that
most cases of schizophrenia will involve a
variant of large effect. As such variants are
likely to be rapidly selected against, they are
also likely to be quite rare. The findings of
specific, gene-disrupting CNVs or mutations in
individual genes in schizophrenia cases by Need
et al. and numerous other groups support this
idea. Excitingly, they also have highlighted
specific molecules and biological pathways that
provide molecular entry points to elucidate
pathogenic mechanisms. The possible convergence
on genes interacting with DISC1, including PCM1
and NDE1 in the current study, provides further
support for the importance of this pathway,
though, clearly, there may be many other ways to
disrupt neural development or function that could
lead to schizophrenia. (Conversely, it is
becoming clearer that many of the putative
causative mutations identified so far predispose
to multiple psychiatric or neurological
conditions.)

Despite the likely involvement of rare variants
in most cases of schizophrenia, it remains
possible that common alleles could have a
modifying influence on risk—indeed, one early
paper commonly cited as supporting a polygenic
model for schizophrenia actually provided strong
support for a model of a single gene of large
effect and two to three modifiers (Risch, 1990). A
rare variants/common modifiers model would be
consistent with the body of literature on
modifying genes in model organisms, where effects
of genetic background on the phenotypic
expression of particular mutations are quite
common and can sometimes be large (Nadeau, 2001).
Whether such genetic background effects would be
mediated by common or rare variants is another
question—there is certainly good reason to
think that rare or even private mutations may
make a larger contribution to phenotypic variance
than previously suspected (Ng et al., 2008; Ji et
al., 2008).

Nevertheless, common variants are also likely to
be involved, and these effects might be detectable
in large association studies, though they would
be expected to be diluted across genotypes. This
might explain inconsistent findings of
association of common variants with disease state
for various genes, including COMT, BDNF, and
DISC1, for example. This issue has led some to
look for association of variants in these genes
with endophenotypes of schizophrenia in the
general population—psychological or
physiological traits that are heritable and
affected by the symptoms of the disease, such as
working memory, executive function, or, in the
study by Tomppo et al., social interaction.

These approaches have tended to lead to
statistically stronger and more consistent
associations and are undoubtedly revealing genes
and mechanisms contributing to normal variation
in many psychological traits. How this relates
to their potential involvement in disease
etiology is far from clear, however. The
implication of the endophenotype model is that
the disorder itself emerges due to the
combination of minor effects on multiple symptom
parameters (Gottesman and Gould, 2003;
Meyer-Lindenberg and Weinberger, 2006). An
alternative interpretation is that these common
variants may modify the phenotypic expression of
some other rare variant, either due to their
demonstrated effect on the psychological trait in
question or through a more fundamental
biochemical interaction, but that in the absence
of such a variant of large effect, no combination
of common alleles would lead to disease.